Benefits and risks of clopidogrel use in patients with coronary artery disease: evidence from randomized studies and registries.

BACKGROUND: Aggressive antiplatelet treatment is currently an established practice in patients with coronary artery disease.

OBJECTIVE: This article discusses the evidence from clinical trials and registries concerning the benefits and risks of clopidogrel in relation to the dose and timing of treatment and its use in particular patient populations (stratified by risk factors for major adverse cardiovascular events).

METHODS: Human clinical trials, registries, and in vitro human platelet studies were identified through searches of MEDLINE, Scopus, Google Scholar, and ClinicalTrials.gov (January 1980-July 2008) using the terms clopidogrel in coronary artery disease, clopidogrel loading dose, clopidogrel pretreatment, and antiplatelet therapy for coronary artery disease. For inclusion in the review, publications had to compare clopidogrel administered at different doses and times across the spectrum of patients with coronary artery disease; present outcome data on mortality, reinfarction, stroke, or their combination; and report safety data pertaining to bleeding risk.

RESULTS: The results of randomized trials support the benefit of administering a 300-mg loading dose of clopidogrel as part of both conservative and invasive strategies for the management of acute coronary syndromes (ACS). In a small randomized trial in patients with non-ST-segment elevation ACS, pretreatment with clopidogrel 600 mg >12 hours before coronary stenting was associated with significantly fewer major adverse cardiovascular events compared with pretreatment with clopidogrel 300 mg (P = 0.020). A randomized trial in patients with ACS undergoing percutaneous coronary intervention (PCI) reported a significant reduction in ischemic risk with prasugrel (60-mg loading dose, 10-mg/d maintenance dose) compared with clopidogrel (300-mg loading dose, 75-mg/d maintenance dose) (P < 0.001); however, the clinical benefit with prasugrel was accompanied by a significant increase in the risk of life-threatening bleeding (P = 0.01). Pretreatment with a 300-mg clopidogrel loading dose administered at least 15 hours before elective PCI was associated with a significant reduction in periprocedural ischemic events compared with 75 mg given after PCI (P = 0.028). In another randomized trial in patients undergoing elective PCI, pretreatment with clopidogrel 600 mg before diagnostic catheterization was associated with a significantly increased risk of minor bleeding complications (P = 0.027) without a significant benefit in terms of the primary ischemic end point. Data from registries support the use of a 300-mg loading dose of clopidogrel for the standard care of patients with ACS and indicate no significant benefit for pretreatment with loading doses >300 mg. One study of registry data found that pretreatment with clopidogrel 300 mg before elective PCI was associated with a significant reduction in major adverse cardiovascular events compared with a loading dose given immediately before or after the intervention (P = 0.002).

CONCLUSIONS: Suppression of platelet activity through the use of antithrombotic agents should be balanced against the risk of atherothrombotic events. In patients with ACS, inhibition of platelet activation beyond that produced by clopidogrel 600 mg has been associated with an increased bleeding risk. In patients undergoing elective PCI, pretreatment with clopidogrel 300 mg administered >15 hours before the procedure achieved the optimal risk-benefit ratio. In cases of unplanned PCI, administration of clopidogrel 600 mg immediately after diagnostic catheterization was well tolerated and effective.